Liver disorders are still the major health hazards both in urban and rural areas of the world. Despite scientific advances in our understanding of hepatotoxicity, and leads provided by traditional system of medicine, we do not have yet any effective entities to cure liver derangement more importantly those which are caused by a variety of drugs. The Indian Council of Medical Research, New Delhi in its revised research programme on traditional medicines, has adopted liver diseases as one among six thrust areas for multidisciplinary study.
The disorders of the liver may be classified into acute or chronic hepatitis (inflammatory liver diseases), hepatosis (non-inflammatory disorders). The acute condition is often followed by liver cirrhosis as well as hepatic coma with grave prognosis. Liver cirrhosis as such accounts amongst the ten top fatal diseases in the world. Exposure of humans to a variety of agents such as chemicals and drugs (xenobiotics), many natural compounds, viral and bacterial pathogens with attendant predisposable conditions, etc. are considered responsible for hepatic insufficiency.
There are large group of drugs which on repeated administration produce liver toxicity. These are mediated primarily by bioactivation so that the products of parent drug are toxic. Another class of drugs induce toxicity by causing membrane rupture or DNA damage and by interfering with protein synthesis. One of the important categories of drugs are the anti-TB drugs which when taken regularly cause hepatotoxicity.
Tuberculosis is prevelent in all counteries of the world—tropical, subtropical and colder regions. The chemotherapy of tuberculosis is important and challenging, because the disease is often chronic and the toxicity due to anti-TB drugs pose therapeutic problems. The disorders of the liver caused during the treatment of tuberculosis, by known antimicrobial agents range from jaundice to the fibrosis of the liver. Several cases progress to the chronic form of disease or have a fulminant course and prove fatal. Three drugs i.e., rifampicin, pyrazinamide and isoniazid comprise first choice treatment of tuberculosis. These are to be administered for long period of time and produce liver dysfunction leading to toxicity.
Jaundice is amongst the most prominent incidence of their adverse raections. The characteristic pathology is the bridging and multilobular necrosis. Hypersensitivity to these drugs leads to hepatitis. Multidrug treatment also poses special problems. Rifampicin causes liver damage. Disturbances in liver function is more if it is combined with isoniazid. Pyrazinamide is the most toxic of the three anti-TB drugs. Continuation of the drugs in combination after symptoms of hepatic dysfunction have appeared tends to increase further the severity of damage. Severe hepatic injury leading to death has been reported in patients receiving these drugs (Slivka, I L, Farmakol Toksikol-1989: 52;82–85)
In our traditional system of medicines (Ayurveda), use of several medicinal plants have been prescribed for alleviating liver disorders. There are nearly forty indigenous polyherbal formulations from more than 100 plants enjoying reputation of being hepatoprotectives. However, none have been specified as a therapeutic agent, which is able to protect the liver from injury due to treatment of anti-TB drugs. This owes partly to the fact that reports are scanty with regard to evaluation of plants/plant products, which would seem focussed specially against hepatic injury caused by drugs which produce toxicity as a result of bioactivation.
There is thus a growing interest in the development of herbal entities considered relatively safe for alleviating liver disorders specifically caused by the anti-TB drugs.
Emblica officinalis Gaertn. (Hindi: Amla) (Euphorbiaceae) is widespread in India, Ceylon, Malaya and China. The tree is common in mixed deciduous forests of India ascending to 4500 ft on the hills, cultivated in gardens and homeyards. It is a small or medium sized deciduous tree, fruits depressed globose, ½ to 1 inch in diameter, fleshy, and contains six trigonows seeds. The fruit is sour and is occasionally eaten raw. The fruit pulp contains (%); moistre 81.2, protein 0.5, fat 0.1, mineral matter 0.7, Ca 0.005, Phosphorus 0.02 and Iron 1.2 mg/100 gm, nicotinic acid 0.2 mg/100 gm, vitamin C 600 mg/100 mg. (Medicinal plants of India, Satyavati et al (ed.), ICMR, new Delhi, 1976, p 377). The potent vitamin C-like activity has been located in the low molecular weight hydrolysable tannins. Four such compounds emblicanin-A, emblicanin-B, punigluconin and pedunculagin have been isolated from the fresh pericarp. The first two compounds are naturally occurring galloellagi-tannins (Ghosal, et al, IndJChem, 1996:353:941–948; Bhattacharya et al, Phytomedicine, 2000: 7: 173–175)
The fruit is acrid, cooling, and diuretic. Dried fruit is useful in haemorrhage, diarrhoea and dysentry. It has been extensively use in anemia, liver diseases and dyspepsea. A fermented liquor prepared from the fruits is used in jaundice. Fruits are a reputed Ayurvedic rasayan (revitaliser, biological response modifier) (Sharma P. V. Dravyaguna vijnana, Chaukhamba Sanskrit Sansthan, Varanasi, 1978). Several pharmacological properties are also reported. Leaf extracts have been found to be anti-inflammatory (Summanen et al, Planta Medica, 1993:59: 666), antioxidant (Jose. and Kuttan, Clin. Biochem. Nutr, 1995:19:63–70), hypolipidemic (Mathw:eta\,JEthnopharmacol, 1996:50:61–68), cell growth inhibition (Psatima et al, ACS Symp. Ser, 1998, p701). Hepatoprotective activity of Emblica officinalis extracts against a chemical viz., carbon tetrachoride induced liver toxicity has been demonstrated (Jose J K & Kutten R, J. Ethnopharmacology 2000:72; 135–40; Bhattacharya et al, Phytomerdicine 2000:7:173–5).
The article by Sharma et al (Hum Exp. toxicol 2000:19; 337–84) suggests that Emblica Officinalis prevents genotoxicity induced by benzopyrines. Benzopyrene is one of the prominent environmental carcinogen which is a specific substrate for CYP 450 1A1. Both are clastogenic. However, the liver toxicity produced by the drugs including anti-TB drugs is dependent on a great measure to their bio-activation through multiple CYP isoforms, the most prominent being CYP450 3A4. There are several agents, which reduce CYP levels or reverse the micronuclei formation but are not hepatoprotective. To cite an example, applicants have developed a molecule, piperine which is a specific inhibitor of CYP 450 1A1, but is not hepatoprotective. Similarly, there are several known compounds, which reverse the genotoxicity but are not hepatoprotective. Therefore the decrease in CYP 1A1 or reversal of clastrogencity can not be construed as hepatoprotection. For example, jaundice (hepato-biliary dysfunction) has not been correlated with genotoxicity, rather it may be an early event in the onset of liver toxicity. In the present article, a casual relationship between CYP decrease or genotoxicity has not been related to attenuation of clinical pathology usually seen in symptoms of hepatotoxicity.
In the present invention, the Applicants provide protection against hepatotoxicity produced by all such drugs, which are bio-activated by multiple CYP isoforms as indicated by clinical parameters in serum/liver. Besides, we claim that the clinical parameters showing toxicity are reversed even if the symptoms of genotoxicity may not begin to appear. For example decrease in abnormal rise of serum Bilirubin, which may be attributed to a protective effect also due to other cellular factors such as membrane stabilization, as revealed in primary monolayer cultures of liver cells.
Thus, we claim preparations from Emblica officinalis which are superior so far as their systemic effects are manifested in clinical profile (serum/liver parameters) which correlate to their hepatoprotective profile.